Document Type: Original Article

Authors

1 Division of Cancer Research, Regional Cancer Centre, Trivandrum, India

2 Gulf Medical University, Ajman, UAE

3 Division of Medical Oncology, Regional Cancer Centre, Trivandrum, India

Abstract

Background: Fms-like tyrosine kinase 3 is a tyrosine kinase receptor that plays animportant role in proliferation and differentiation of hematopoietic stem cells. Internaltandem duplication and tyrosine kinase domain mutation are the two most commontypes of fms-like tyrosine kinase 3 mutations frequently reported in acute myeloidleukemia associated with pathogenesis of this disease. The present study investigates the prevalence and distribution pattern in different acute myeloid leukemia sub- and cytogenetic groups, the association with clinical parameters and the prognostic importance of these mutations in acute myeloid leukemia patients from South India. Methods:Mutation analysis was performed in 276 de novo acute myeloid leukemiapatients by polymerase chain reaction restriction fragment length polymorphism using specific restriction enzymes followed by sequencing to confirm the mutations. Kaplan-Meier survival analysis was performed to detect the prognosis. Results: Fms-like tyrosine kinase 3 internal tandem duplication mutations wereobserved in 20%, tyrosine kinase domain mutation in 4% and dual mutations in 0.3%of the analyzed cases. The internal tandem duplication mutations ranged from 15-107 nucleotides with the majority at the juxta membrane domain of the receptor. Three types of tyrosine kinase domain point mutations were identified: D835Y, D835H and D835V. We observed a significant association between fms-like tyrosine kinase 3 mutations and increased WBC and LDH counts (P<0.001) and blast percentage but not with age, gender and FAB subtypes. A significant association with normal karyotype was observed for the mutants (P=0.002). Survival analysis revealed that the fms-like tyrosine kinase 3 gene mutation was a negative prognostic marker for acute myeloid leukemia patients. The risk stratified analysis showed the mutation to be a risk factor for the intermediate karyotype group, especially for those with normal cytogenetics. Conclusion: Our results indicate that the presence of an fms-like tyrosine kinase3 mutation can serve as a valuable prognostic marker in this subgroup of patients,allowing stratification for risk-directed therapy.